Psychotic Experiences Share Genetic Liability in Multiple Disorders

Evidence suggests a shared genetic liability between psychotic experiences and several psychiatric disorders, including but not limited to schizophrenia, according to study results published in JAMA Psychiatry.

The investigators of this large population-based cohort study sought to identify genetic loci associated with psychotic experiences and to determine if the genetic liability to psychotic experiences is shared with schizophrenia and other neuropsychiatric disorders.

In the United Kingdom, the study included 127,966 participants with a mean age of 64 years who reported any psychotic experience (n=6123), including distressing psychotic experiences (n=2143), multiple occurrences of psychotic experiences (n=3337), and no psychotic experiences (n=121,843). Investigators conducted genome-wide association studies of the 4 psychotic experience phenotypes to identify novel genetic loci associated with psychotic experiences. Genetic data from participants provided by the UK Biobank were further analyzed for genetic correlation, polygenetic risk scores, and copy number variations.

In genome-wide association studies, investigators identified 4 loci that were significantly associated with psychotic experiences. These included a locus in Ankyrin-3 associated with any psychotic experience (odds ratio [OR] 1.16; 95% CI, 1.10-1.23; P =3.06×10⁻⁸) and a locus in the cannabinoid receptor 2 gene associated with distressing psychotic experiences (OR 0.66; 95% CI, 0.56-0.78; P =3.78×10⁻⁸). Participants reporting multiple occurrences of psychotic experiences were not associated with a specific genetic variant. Psychotic experiences were, however, found to be heritable because any psychotic experience was associated with low single-nucleotide polymorphism-based heritability estimates.

The investigators found significant genetic correlations between psychotic experiences and major depressive disorder, autism spectrum disorder, attention deficit hyperactivity disorder, and schizophrenia. Polygenic risk scores further revealed weak associations between psychotic experiences and genetic liability for schizophrenia (OR 1.09; 95% CI, 1.06-1.12; P =2.96×10⁻¹¹), major depressive disorder (OR 1.16; 95% CI, 1.13-1.19; P =1.48×10⁻³⁰), bipolar disorder (OR 1.07; 95% CI, 1.04-1.10; P =5.11×10⁻⁷), attention deficit hyperactivity disorder (OR 1.06; 95% CI, 1.03-1.09; P =5.73 x 10⁻⁶), and autism spectrum disorder (OR 1.07; 95% CI, 1.04-1.10; P =1.34 x 10⁻⁵). These associations, however, were stronger for the distressing psychotic experiences phenotype. Participants reporting distressing psychotic experiences also had an increased burden of copy number variations previously associated with schizophrenia (OR 2.04; 95% CI, 1.39-2.98; P =2.4×10⁻⁴) and neurodevelopmental disorders (OR 1.75; 95% CI, 1.24-2.48; P =1.41×10⁻³).

Study limitations included the possibility that some participants with psychotic disorders were not identified and remained in the analysis, and the use of a retrospective self-report measure of lifetime psychotic experiences from an online questionnaire. Furthermore, the participants recruited to the UK Biobank were potentially limited by selection bias and may not be representative of the general population; all duplicate data sets from the UK Biobank may not have been identified and thus included in analysis.

The investigators suggested that psychotic experiences are associated with a general risk for mental health disorders, not just schizophrenia, in which these findings support a shared genetic liability between psychotic experiences and multiple disorders, including schizophrenia, major depression, bipolar disorder, and neurodevelopment disorders.

Multiple authors declared affiliations with the pharmaceutical industry. Please see the reference for a complete list of authors’ disclosures.

Reference

Legge SE, Jones HJ, Kendall KM, et al. Association of genetic liability to psychotic experiences with neuropsychotic disorders and traits [published online September 25, 2019]. JAMA Psychiatry. doi: 10.001/jamapsychiatry.2019.2508